Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P10415 (Bcl-2)
33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reduction in serum prostate-specific antigen (PSA) levels has been proposed as an endpoint biomarker for hormone-refractory human prostate cancer intervention. We examined whether a flavonoid antioxidant silibinin (an active constituent of milk thistle) decreases PSA levels in hormone-refractory human prostate carcinoma LNCaP cells and whether this effect has biological relevance. Silibinin treatment of cells grown in serum resulted in a significant decrease in both intracellular and secreted forms of PSA concomitant with a highly significant to complete inhibition of cell growth via a G1 arrest in cell cycle progression. Treatment of cells grown in charcoal-stripped serum and 5alpha-dihydrotestosterone showed that the observed effects of silibinin are those involving androgen-stimulated PSA expression and cell growth. Silibinin-induced G1 arrest was associated with a marked decrease in the kinase activity of cyclin-dependent kinases (CDKs) and associated cyclins because of a highly significant decrease in cyclin D1, CDK4, and CDK6 levels and an induction of Cip1/p21 and Kip1/p27 followed by their increased binding with CDK2. Silibinin treatment of cells did not result in apoptosis and changes in p53 and bcl2, suggesting that the observed increase in Cip1/p21 is a p53-independent effect that does not lead to an apoptotic cell death pathway. Conversely, silibinin treatment resulted in a significant neuroendocrine differentiation of LNCaP cells as an alternative pathway after Cip1/p21 induction and G1 arrest. Together, these results suggest that silibinin could be a useful agent for the intervention of hormone-refractory human prostate cancer.
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PMID:Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: implications for prostate cancer intervention. 1037 42

An increasing incidence of human skin cancer and other adverse effects of solar ultraviolet (UV) radiation enhance the need for novel chemoprevention strategies. Here, we have studied the effect of silibinin on UVB-induced apoptosis in HaCaT cells. Silibinin strongly prevented lower doses (15 and 30 mJ/cm2) of UVB-induced apoptosis, as observed by a reversal in UVB-caused poly(ADP-ribose) polymerase (PARP) cleavage, caspase 9 activation and an increase in apoptotic cells. UVB-induced PARP cleavage was also abolished by all caspase inhibitor, suggesting that it is a caspase-dependent effect. In other studies, silibinin restored UVB-caused depletion of a protein inhibitor of apoptosis, survivin, concomitant with up-regulation of transcription factor nuclear factor kappaB DNA binding activity, without any noticeable effect on UVB-caused activated protein-1 activation. Further, silibinin treatment up-regulated UVB-induced extracellular signal regulated kinase 1/2 phosphorylation, suggesting a possible role as a survival event in the protective effect of silibinin. In other studies, silibinin caused a moderate increase in phospho-Bcl-2, without any noticeable changes in total Bcl-2 levels, and down-regulated bax levels moderately. Silibinin also caused a strong decrease in Bad heterodimerization with Bclx(L), which was consistent with an increased translocation of Bclx(L) to the mitochondria from the cytosol. Consistent with its protective effect on UVB-caused apoptosis, silibinin also increased S phase arrest, possibly providing a prolonged time for efficient DNA repair. Interestingly, the protective effects of silibinin in HaCaT cells were lost at a higher dose of UVB (120 mJ/cm2) and instead it further enhanced UVB-caused apoptosis together with a strong decrease in UVB-caused activated protein-1 activation. Together, these results clearly demonstrate the dual efficacy of silibinin in protecting or enhancing UVB-caused apoptosis in the same cellular system and suggest that silibinin possibly works as a UVB damage sensor to exert its biological action.
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PMID:Dual efficacy of silibinin in protecting or enhancing ultraviolet B radiation-caused apoptosis in HaCaT human immortalized keratinocytes. 1455 14

Silibinin, the flavonoid found in the milk thistle, has been shown to suppress cell growth and exhibit anti-cancer effects. Some flavonoids were reported to inhibit angiogenesis which is essential for tumor growth and metastasis. In this study, to clarify the underlying mechanisms for the anti-cancer effect of silibinin, we examined the effects of silibinin on human endothelial ECV304 cells. Silibinin was found to suppress the growth and induce the apoptosis of ECV304 cells. The induction of apoptosis by silibinin was confirmed by ladder-patterned DNA fragmentation, cleaved and condensed nuclear chromatin and DNA hypoploidy. Silibinin could effectively inhibit constitutive NF-kappaB activation as revealed by electrophoretic mobility shift assay and NF-kappaB-dependent luciferase reporter study. Consistent with this, silibinin treatment resulted in a significant decrease in the nuclear level of p65 subunit of NF-kappaB. In addition, silibinin treatment caused a change in the ratio of Bax/Bcl-2 in a manner that favors apoptosis. Silibinin also induced the cytochrome c release, activation of caspase-3 and caspase-9 and cleavage of PARP. These results suggest that silibinin may exert, at least partly, its anti-cancer effect by inhibiting angiogenesis through induction of endothelial apoptosis via modulation of NF-kappaB, Bcl-2 family and caspases.
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PMID:Involvement of NF-kappaB and caspases in silibinin-induced apoptosis of endothelial cells. 1465 75

Several recent studies by us have shown the strong chemopreventive efficacy of silibinin against both ultraviolet B (UVB) radiation and chemical carcinogen-induced tumorigenesis in mouse skin models. The molecular mechanisms underlying silibinin protective efficacy, however, are not completely known. Here, we examined the effect of silibinin on UVB-caused apoptosis in human epidermoid carcinoma A431 cells. Irradiation of cells with different doses of UVB (5-100 mJ/cm2) and different time periods (0.5-24h) resulted in a dose- and time-dependent increase in apoptosis (P < 0.05-0.001). Silibinin (100-200 microM) pre-treatment, however, resulted in an increase in UVB-induced apoptosis (P < 0.05-0.001); interestingly, its post-treatment caused a decrease in UVB-induced apoptosis (P < 0.05-0.001). A similar pattern in the activation of caspases-9, -3, and -7 was observed with these silibinin treatments. Further, silibinin treatment prior to or immediately after UVB exposure altered Bcl-2, Bax, Bak, and cytochrome c levels in mitochondria and cytosol in favor of or against apoptosis, respectively. Silibinin treatment prior to UVB also increased the activation of mitogen/stress activated protein kinases Erk1/2, JNK, and p38 kinase as compared to its post-treatment. Together, for the first time, our results demonstrate the role of mitochondrial apoptotic machinery and MAPK signaling cascade in silibinin-caused increase as well as protection in UVB-induced apoptosis in A431 cells, and suggest that similar mechanisms might be involved in preventive efficacy of silibinin against UVB-induced skin tumorigenesis.
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PMID:Silibinin modulates UVB-induced apoptosis via mitochondrial proteins, caspases activation, and mitogen-activated protein kinase signaling in human epidermoid carcinoma A431 cells. 1520 19

Silymarin, a plant flavonoid from milk thistle (Silybum marianum [L.] GAERTNER) was first evaluated for its protective effect against UV irradiation-induced apoptosis in human malignant melanoma cells (A375-S2 cells). Treatment with silymarin 500 microM for 12 h significantly inhibited UV irradiation (2.4 J/cm(2), 5 min)-induced apoptosis in A375-S2 cells. Activities of caspase-9 and caspase-3 in UV-irradiated A375-S2 cells were effectively reduced by silymarin in a dose-dependent manner, while the expression of the inhibitor of caspase-activated DNase (ICAD), protein expression of Bcl-x(L) (Bcl-2 family member), and the activity of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) were increased simultaneously. It is suggested that the inhibitory effect of silymarin is exerted by blockage of the caspase/ICAD pathway after increased expression of Bcl-x(L) protein and activation of the ERK/MAPK pathway.
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PMID:Silymarin prevents UV irradiation-induced A375-S2 cell apoptosis. 1525 35

Silymarin, a plant flavonoid, has been shown to inhibit skin carcinogenesis in mice. However, the mechanism responsible for the anti-skin carcinogenic effects of silymarin is not clearly understood. Here, we report that treatment of JB6 C141 cells (preneoplastic epidermal keratinocytes) and p53+/+ fibroblasts with silymarin and silibinin (a major constituent of silymarin) resulted in a dose-dependent inhibition of cell viability and induction of apoptosis in an identical manner. Silymarin-induced apoptosis was determined by fluorescence staining (8-64% apoptosis) and flow cytometry (12-76% apoptosis). The silymarin-induced apoptosis was primarily p53 dependent because apoptosis occurred to a much greater extent in the cells expressing wild-type p53 (p53+/+, 9-61%) than in p53-deficient cells (p53-/-, 6-20%). The induction of apoptosis in JB6 C141 cells was associated with increased expression of the tumor suppressor protein, p53, and its phosphorylation at Ser15. The constitutive expression of antiapoptotic proteins Bcl-2 and Bcl-xl were decreased after silymarin treatment, whereas the expression of the proapoptotic protein Bax was increased. There was a shift in Bax/Bcl-2 ratio in favor of apoptotic signal in silymarin-treated cells, which resulted in increased levels of cytochrome c release, apoptotic protease-activating factor-1, and cleaved caspase-3 and poly(ADP-ribose) polymerase in JB6 C141 cells. The shift in Bax/Bcl-2 ratio was more prominent in p53+/+ fibroblasts than in p53-/- cells. Silymarin-induced apoptosis was blocked by the caspase inhibitor (Z-VAD-FMK) in JB6 C141 cells which suggested the role of caspase activation in the induction of apoptosis. These observations show that silymarin-induced apoptosis is primarily p53 dependent and mediated through the activation of caspase-3.
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PMID:Silymarin induces apoptosis primarily through a p53-dependent pathway involving Bcl-2/Bax, cytochrome c release, and caspase activation. 1571 92

The cytotoxic activity of Brostallicin was previously shown to be enhanced in the presence of high glutathione and glutathione transferase levels. We hypothesized that thiol antioxidants, N-acetylcysteine and Silibinin, could potentiate Brostallicin's cytotoxicity in a similar way. HepG2 and CNE-2 cells were treated with N-acetylcysteine, Silibinin and Brostallicin, either alone or in combination. Surprisingly, we found that NAC and Silibinin had adverse effects on Brostallicin's cytotoxicity. The mechanism underlying the interaction involved the apoptotic pathway as we demonstrated an increase in Bcl-2 protein levels and decrease in caspase 3 activity with the Silibinin-Brostallicin combination.
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PMID:Combination of thiol antioxidant Silibinin with Brostallicin is associated with increase in the anti-apoptotic protein Bcl-2 and decrease in caspase 3 activity. 1611 2

Silymarin was proved to have a protective effect of UV-induced A375-S2 cell apoptosis in our previous research. In this study, its pro-apoptotic and anti-apoptotic activities on human cervical cancer (HeLa) cells in vitro were investigated. Silymarin induced HeLa cell death through both apoptotic and necrotic pathways. At low doses (below 80 micromol l-1), it induced cell apoptosis, but caused necrosis at high dose (160 micromol l-1). Silymarin induced typical chromatin condensation and nuclear fragmentation as a hallmark of apoptosis. In this case, mitochondrial Bcl-2 family, Bcl-2 and Bax, were not involved in apoptotic effects; however, silymarin-induced cell death was regulated by the activation of p38 and JNK MAPKs. We also found that pan-caspase inhibitor and caspase-3 inhibitor could not antagonise silymarin-induced apoptosis. Therefore, silymarin induced and augmented HeLa cell apoptosis through p38/JNK MAPKs in the serum-free medium.
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PMID:Silymarin augments human cervical cancer HeLa cell apoptosis via P38/JNK MAPK pathways in serum-free medium. 1617 2

Silymarin is a polyphenolic flavonoid derived from milk thistle (Silybum marianum) and has anti-inflammatory, cytoprotective as well as anticarcinogenic effects [Manna, S.K., Mukhopadlhyay, A., Van, N.T., Aggarwal, B., Silymarin suppresses TNF-induced activation of NF-kappaB, c-Jun N-terminal kinase, and apoptosis. J. Immunol. 1999; 163, 6800-6809.]. In this study, we assessed the effect of silymarin on ultraviolet light (UV)-induced cell apoptosis in human malignant melanoma, A375-S2 cells. Silymarin pre-treatment reversed the effect of UV irradiation on the expression of phosphorylated Akt and phosphorylated p53 (regulated by Akt activation), followed by down-regulation of Bax and up-regulated expressions of Bcl-2 and Bcl-xL proteins in UV-irradiated A375-S2 cells. Akt inhibitor decreased the viability of UV-irradiated cells which was treated with silymarin. In addition, the effect of UV irradiation on the phosphorylation of mitogen-activated protein kinase (MAPK) family members [extracellular signal-regulated kinase (ERK), p38 and c-Jun N-terminal kinase (JNK)] was also reversed by silymarin. Moreover, ERK inhibitor (PD98059) and p38 inhibitor (SB203580) augmented UV-induced apoptosis in silymarin treated A375-S2 cells. Consequently, silymarin partially reduced UV-induced apoptosis by activating the Akt pathway, and silymarin's protective effect was also exerted by MAPK family members.
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PMID:The roles of Akt and MAPK family members in silymarin's protection against UV-induced A375-S2 cell apoptosis. 1639 23

Silibinin, derived from the milk thistle plant, Silybum marianum, has been traditionally used as an antihepatotoxic agent for the treatment of liver disease. Our preliminary study demonstrated that silibinin has protected rat cardiac myocytes against beta-adrenergic agonist isoproterenol-induced injury through resuming mitochondrial function and regulating the expression of SIRT1 and Bcl-2 family members. In this study, we investigate whether silibinin has anti-apoptotic effect on isoproterenol-treated rat cardiac myocytes. DNA damage, detected by the TUNEL and DNA fragmentation assay, was diminished after treatment of silibinin. Results of nitrite and Western blot assays showed that the amount of NO and the expression of iNOS were decreased after treatment with silibinin, while the expression of procaspase-3 and digestion of caspase-3 substrates, the inhibitor of caspase-activated DNase (ICAD) and poly-(ADP-ribose) polymerase (PARP), were increased simultaneously. The DNA damage was reversed by down-regulation of p53 phosphorylation after treatment with silibinin. Result of flowcytometric analysis showed that the cell cycle was not affected, and the expression of cell cycle regulatory protein p21 also had no change. Consequently, silibinin protected cardiac myocytes against isoproterenol-induced DNA damage through caspase pathway and the expression of p53, but independent on regulation of cell cycle.
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PMID:Silibinin protects rat cardiac myocyte from isoproterenol-induced DNA damage independent on regulation of cell cycle. 1694 6


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